Heart Lung Institute, The Prince Charles Hospital, Chermside, QLD, Australia.
Cardio-Vascular Molecular & Therapeutics Translational Research Group, University of Queensland, Brisbane, QLD, Australia.
Pharmacol Res Perspect. 2021 May;9(3):e00760. doi: 10.1002/prp2.760.
Omecamtiv mecarbil (OM) is a novel medicine for systolic heart failure, targeting myosin to enhance cardiomyocyte performance. To assist translation to clinical practice we investigated OMs effect on explanted human failing hearts, specifically; contractile dynamics, interaction with the β -adrenoceptor (AR) agonist (-)-noradrenaline and spontaneous contractions. Left and right ventricular trabeculae from 13 explanted failing hearts, and trabeculae from 58 right atrial appendages of non-failing hearts, were incubated with or without a single concentration of OM for 120 min. Time to peak force (TPF) and 50% relaxation (t ) were recorded. In other experiments, trabeculae were observed for spontaneous contractions and cumulative concentration-effect curves were established to (-)-noradrenaline at β -ARs in the absence or presence of OM. OM prolonged TPF and t in ventricular trabeculae (600 nM, 2 µM, p < .001). OM had no significant inotropic effect but reduced time dependent deterioration in contractile strength compared to control (p < .001). OM did not affect the generation of spontaneous contractions. The potency of (-)-noradrenaline (pEC 6.05 ± 0.10), for inotropic effect, was unchanged in the presence of OM 600 nM or 2 µM. Co-incubation with (-)-noradrenaline reduced TPF and t , reversing the negative diastolic effects of OM. OM, at both 600 nM and 2 µM, preserved contractile force in left ventricular trabeculae, but imparted negative diastolic effects in trabeculae from human failing heart. (-)-Noradrenaline reversed the negative diastolic effects, co-administration may limit the titration of inotropes by reducing the threshold for ischemic side effects.
奥马环巴（OM）是一种新型的治疗收缩性心力衰竭的药物，其作用靶点是肌球蛋白，以增强心肌细胞的性能。为了帮助将其转化为临床实践，我们研究了 OM 对提取的人类衰竭心脏的影响，特别是收缩动力学、与β-肾上腺素受体（AR）激动剂（-）去甲肾上腺素的相互作用以及自发性收缩。用或不用 OM 的单一浓度孵育 13 个提取的衰竭心脏的左心室和右心室小梁，以及 58 个非衰竭心脏的右心房附件的小梁 120 分钟。记录达到峰值力（TPF）和 50%松弛（t）的时间。在其他实验中，观察小梁的自发性收缩，并在不存在或存在 OM 的情况下，建立（-）去甲肾上腺素在β-AR 上的累积浓度-效应曲线。OM 延长了心室小梁的 TPF 和 t（600 nM，2 µM，p < 0.001）。OM 对收缩强度没有明显的变力作用，但与对照相比，减少了收缩强度的时间依赖性恶化（p < 0.001）。OM 不影响自发性收缩的产生。（-）去甲肾上腺素的效力（pEC 6.05 ± 0.10），变力作用，在 OM 600 nM 或 2 µM 存在时不变。（-）去甲肾上腺素的共孵育降低了 TPF 和 t ，逆转了 OM 的负性舒张效应。OM 分别在 600 nM 和 2 µM 时保留了左心室小梁的收缩力，但在心力衰竭患者的小梁中产生了负性舒张效应。（-）去甲肾上腺素逆转了负性舒张效应，共同给药可能通过降低缺血副作用的阈值来限制正性肌力药物的滴定。
